Neurodegenerative disorders have provided a challenge for many years, in both basic research and clinical contexts. As an example of such a neurodegenerative disorder, retinitis pigmentosa (RP) is a genetically heterogeneous retinal degeneration characterized by the sequential degeneration of a population of neurons corresponding to rod and cone photoreceptors. The RP first clinical signs are night blindness and narrowing of the peripheral field of vision which progressively worsens to become “tunnel-like”. Eventually, the central vision is reduced to complete blindness in most cases. At a cellular level, the retinal rod photoreceptors involved in night and side visions slowly degenerate. Subsequently, the cone photoreceptors responsible for both color and high-contrast vision, visual acuity, detail perception and normal light vision are similarly affected. The retinal degeneration 1 (rd1) mouse is the most studied animal model for retinitis pigmentosa. It carries a recessive mutation in the rod-specific cGMP phosphodiesterase beta subunit gene leading to rod photoreceptor death through apoptosis (CARTER-DAWSON et al., Invest. Opthalmol. Vis. Sci., vol. 17(6), p: 489-498, 1978; PORTERA-CAILLIAU et al., Proc. Natl. Acad. Sci. U.S.A, vol. 91(3), p: 974-978, 1994) followed by cone death presumably through lack of trophic support (MOHAND-SAID et al., Proc. Natl. Acad. Sci. U.S.A, vol. 95(14), p: 8357-8362, 1998). Accordingly, the technical problem underlying the present invention is to provide novel compounds having neurotrophic activities, which compounds are suitable for the treatment of neurodegenerative disorders such as retinitis pigmentosa for which no treatment is actually available.
The RdCVF gene, also called thioredoxin-like 6 (Txn16) or Nucleoredoxin-like 1 (Nxnl1), encodes the Q8VC33 UniProt [6] protein, which has limited similarity to the thioredoxin superfamily and which exerts trophic activity on cone photoreceptors (LEVEILLARD et al., Nat. Genet. vol. 36(7), p: 755-759, 2004). Thioredoxins (TXN) are usually small proteins which can be involved with pleiotropic activities such as redox control, regulation of apoptosis and cytokine activity (HOLMGREN, Annu. Rev. Biochem., vol. 54, p: 237-271, 1985; HOLMGREN, J. Biol. Chem., vol. 264(24), p: 13963-13966, 1989; ARNER and HOLMGREN, Eur. J. Biochem., vol. 267(20), p: 6102-6109, 2000). The TXN conserved active site contains two distinct cysteines (CXXC) that contribute to a thiol-oxydoreductase activity (ARNER and HOLMGREN, 2000, above-mentioned; POWIS and MONTFORT, Annu. Rev. Pharmacol. Toxicol., vol. 41, p: 261-295, 2001) catalyzes the reduction of disulfide bonds in multiple substrate proteins (HOLMGREN, J. Biol. Chem., vol. 254(18), p: 9113-9119, 1979; HOLMGREN, J. Biol. Chem., vol. 254(19), p: 9627-9632, 1979). The RdCVF gene encodes two products via alternative splicing: a full length protein and a C-terminal post-transcriptionally truncated protein sharing similarities with TRX80. This latter form of human thioredoxin-1 (Txn) (PEKKARI et al., J. Biol. Chem., vol. 275(48), p: 37474-37480, 2000; PEKKARI et al., Blood, vol. 105(4), p: 1598-1605, 2005; LIU et al., Blood, vol. 105(4), p: 1606-1613, 2005) has no thiol-reductase activity but is involved in controlling growth of peripheral mononuclear blood cells (PEKKARI et al., 2000, abovementioned; PEKKARI et al., FEBS Lett., vol. 539(1-3), p: 143-148, 2003). Similar to Txn, RdCVF looks like a bifunctional gene because it encodes both a long form (RdCVF-L, 217 aa, Q8VC33) having a putative thiol-oxydoreductase activity (JEFFERY, Trends Biochem. Sci., vol. 24(1), p: 8-11, 1999; JEFFERY, Trends Genet., vol. 19(8), p: 415-417, 2003) and a short form (RdCVF-S, 109 aa, Q91 W38) with trophic activity for cones but no redox activity.